Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.

Conditions

BRCA 1 Gene Mutation, BRCA 2 Gene Mutation, Breast Cancer Metastatic

Keywords

Breast Cancer, Metastatic, Olaparib, BRCA, PARP inhibitor, HER2, chemotherapy

Brief summary

This open label, randomised, controlled, multi-centre phase III study will assess the efficacy and safety of single agent olaparib vs standard of care based on physician's choice of capecitabine, vinorelbine or eribulin in metastatic breast cancer patients with gBRCA 1/2 mutations.

Balmaña J, Fasching PA, Couch FJ, Delaloge S, Labidi-Galy I, O'Shaughnessy J, Park YH, Eisen AF, You B, Bourgeois H, Gonçalves A, Kemp Z, Swampillai A, Jankowski T, Sohn JH, Poddubskaya E, Mukhametshina G, Aksoy S, Timcheva CV, Park-Simon TW, Antón-Torres A, John E, Baria K, Gibson I, Gelmon KA, LUCY investigators.

2023-12-1911 citations

10.1007/s10549-023-07165-x

200P OlympiAD: Exploratory analysis of olaparib vs capecitabine in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (mBC)

Mark E. Robson, Suzette Delaloge, Susan M. Domchek, Pierfranco Conté, S-A. Im et al. (12 authors)

ESMO Open2023-05-011 citations

10.1016/j.esmoop.2023.101389

BRCA reversion mutations mediated by microhomology-mediated end joining (MMEJ) as a mechanism of resistance to PARP inhibitors in ovarian and breast cancer.

Natalia Lukashchuk, Joshua Armenia, Luis Tobalina, T. Hedley Carr, Tsveta Milenkova et al. (9 authors)

Journal of Clinical Oncology2022-06-0114 citations

10.1200/jco.2022.40.16_suppl.5559

Prevalence of mutations in BRCA and homologous recombination repair genes and real-world standard of care of Asian patients with HER2-negative metastatic breast cancer starting first-line systemic cytotoxic chemotherapy: subgroup analysis of the global BREAKOUT study.

Koh SJ, Ohsumi S, Takahashi M, Fukuma E, Jung KH, Ishida T, Dai MS, Chang CH, Dalvi T, Walker G, Bennett J, O'Shaughnessy J, Balmaña J.

2021-08-317 citations

10.1007/s12282-021-01283-4

Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study.

O'Shaughnessy J, Brezden-Masley C, Cazzaniga M, Dalvi T, Walker G, Bennett J, Ohsumi S.

2020-10-2738 citations

10.1186/s13058-020-01349-9

Olaparib monotherapy for Asian patients with a germline BRCA mutation and HER2-negative metastatic breast cancer: OlympiAD randomized trial subgroup analysis.

Im SA, Xu B, Li W, Robson M, Ouyang Q, Yeh DC, Iwata H, Park YH, Sohn JH, Tseng LM, Goessl C, Wu W, Masuda N.

2020-05-2930 citations

10.1038/s41598-020-63033-4

Real-world clinical effectiveness and safety of olaparib monotherapy in HER2-negative gBRCA-mutated metastatic breast cancer: Phase IIIb LUCY interim analysis.

Karen A. Gelmon, Peter A. Fasching, Fergus J. Couch, Judith Balmaña Gelpí, Suzette Delaloge et al. (10 authors)

Journal of Clinical Oncology2020-05-203 citations

10.1200/jco.2020.38.15_suppl.1087

Abstract PD4-03: OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer

Mark E. Robson, Seock‐Ah Im, Elżbieta Senkus, Binghe Xu, Susan M. Domchek et al. (14 authors)

Cancer Research2020-02-1510 citations

10.1158/1538-7445.sabcs19-pd4-03

Abstract P6-13-05: Impact of olaparib versus chemotherapy on the use of strong pain medications in gBRCA-mutated HER2-negative metastatic breast cancer and associated patient reported outcomes

Chantal Merens, Wendy Bannister, Sven Bergner, Robert Hettle, Charles McCrea et al. (7 authors)

Cancer Research2020-02-151 citations

10.1158/1538-7445.sabcs19-p6-13-05

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial.

Robson M, Ruddy KJ, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Li W, Tung N, Armstrong A, Delaloge S, Bannister W, Goessl C, Degboe A, Hettle R, Conte P.

2019-08-2254 citations

10.1016/j.ejca.2019.06.023

Indirect treatment comparison of the efficacy and safety of olaparib 300 mg tablets BID and talazoparib 1 mg once daily in the treatment of patients with germline BRCA-mutated (gBRCA) HER2-negative metastatic breast cancer.

Charles McCrea, Robert Hettle

Journal of Clinical Oncology2019-05-209 citations

10.1200/jco.2019.37.15_suppl.e12570

OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer.

Robson ME, Tung N, Conte P, Im SA, Senkus E, Xu B, Masuda N, Delaloge S, Li W, Armstrong A, Wu W, Goessl C, Runswick S, Domchek SM.

2019-04-01510 citations

10.1093/annonc/mdz012

LUCY: A phase IIIb, real-world study of olaparib in HER2-negative metastatic breast cancer patients with a BRCA mutation

Karen A. Gelmon, G.P. Walker, Gabrielle Fisher, Susan McCutcheon

Annals of Oncology2018-10-015 citations

10.1093/annonc/mdy272.355

Abstract CT038: OlympiAD final overall survival: Olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm)

Mark E. Robson, Seock‐Ah Im, Elżbieta Senkus, Binghe Xu, Susan M. Domchek et al. (14 authors)

Cancer Research2018-07-013 citations

10.1158/1538-7445.am2018-ct038

Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer (OlympiAD): Efficacy in patients with visceral metastases.

Nadine Tung, Seock‐Ah Im, Elżbieta Senkus, Binghe Xu, Susan M. Domchek et al. (13 authors)

Journal of Clinical Oncology2018-05-2012 citations

10.1200/jco.2018.36.15_suppl.1052

EORTC QLQ-C30 (QLQ-C30) symptoms in patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) receiving olaparib vs chemotherapy treatment of physician’s choice (TPC) in OlympiAD.

Mark E. Robson, Kathryn J. Ruddy, Seock‐Ah Im, Elżbieta Senkus, Binghe Xu et al. (15 authors)

Journal of Clinical Oncology2018-05-203 citations

10.1200/jco.2018.36.15_suppl.1045

Abstract P5-21-12: Tolerability of olaparib monotherapy versus chemotherapy in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: OlympiAD

S. M. Domchek, Mark E. Robson, S-A. Im, Elżbieta Senkus, Binghe Xu et al. (15 authors)

Cancer Research2018-02-153 citations

10.1158/1538-7445.sabcs17-p5-21-12

Abstract P5-21-13: Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial

S-A. Im, Binghe Xu, W. Li, Mark E. Robson, Quchang Ouyang et al. (14 authors)

Cancer Research2018-02-151 citations

10.1158/1538-7445.sabcs17-p5-21-13

Abstract OT3-04-04: LUCY: A phase IIIb, single-arm, open-label multicenter study of olaparib in patients with HER2-negative metastatic breast cancer and a germline BRCA1/2 mutation

Karen A. Gelmon, GP Walker, G V Fisher

Cancer Research2018-02-15

10.1158/1538-7445.sabcs17-ot3-04-04

Drug-Resistant TNBC

Ricardo H. Álvarez

Oncology Times2018-02-09

10.1097/01.cot.0000530874.36363.aa

Patients Experience Fewer Serious Side Effects With PARP Inhibitor

Catlin Nalley

Oncology Times2018-01-31

10.1097/01.cot.0000530522.23834.95

OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm).

Mark E. Robson, Seock‐Ah Im, Elżbieta Senkus, Binghe Xu, Susan M. Domchek et al. (14 authors)

Journal of Clinical Oncology2017-06-1337 citations

10.1200/jco.2017.35.18_suppl.lba4

Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation

Mark E. Robson, Seock‐Ah Im, Elżbieta Senkus, Binghe Xu, Susan M. Domchek et al. (14 authors)

New England Journal of Medicine2017-06-043,073 citations

10.1056/nejmoa1706450

Abstract OT1-1-04: OlympiA, Neo-Olympia and OlympiAD: Randomized phase III trials of olaparib in patients (pts) with breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm)

Mark E. Robson, Andrew Tutt, Judith Balmañà, Bella Kaufman, Judy E. Garber et al. (11 authors)

Cancer Research2015-05-012 citations

10.1158/1538-7445.sabcs14-ot1-1-04

Interventions

DRUGOlaparib

Patients will be administered olaparib orally twice daily (bid) at 300 mg. Two (2) x 150 mg olaparib tablets should be taken at the same times each morning and evening of each day, approximately 12 hours apart with approximately 240 mL of water.

DRUGPhysician's choice chemotherapy

Investigators will declare one of the following regimens: * Capecitabine 2500 mg/m2 po daily (divided in 2 doses) x 14 days, repeat every 21 days * Vinorelbine 30 mg/m2 IV Day 1 and Day 8, repeat every 21 days * Eribulin 1.4 mg/m2 IV Day 1 and Day 8, repeat every 21 days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 99 Years

Healthy volunteers

No

Inclusion criteria

* Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious. * Histologically or cytologically confirmed breast cancer with evidence of metastatic disease. * Prior therapy with an anthracycline and a taxane in either an adjuvant or metastatic setting. * Prior platinum allowed as long as no breast cancer progression occurred on treatment or if given in adjuvant/neoadjuvant setting at least 12 months from last dose to study entry elapsed. * ER/PR breast cancer positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy. * ECOG performance status 0-1. * Adequate bone marrow, kidney and liver function.

Exclusion criteria

* Prior treatment with PARP inhibitor. * Patients with HER2 positive disease. * More than 2 prior lines of chemotherapy for metastatic breast cancer. * Untreated and/or uncontrolled brain metastases. * Prior malignancy unless curatively treated and disease-free for \> 5 years prior to study entry. Prior adequately treated non-melanoma skin cancer, in situ cancer of the cervix, DCIS or stage I grade 1 endometrial cancer allowed. * Known HIV (Human Immunodeficiency Virus) infection. * Pregnant or breast-feeding women.

Design outcomes

Primary

Measure	Time frame	Description
Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)	Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.	Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary

Measure	Time frame	Description
Time to Second Progression or Death (PFS2)	Second progression status reviewed every 8 weeks following the first objective radiological progression as per investigator assessment. Assessed up to a maximum of 30 months.	Time from randomisation to the earliest of the progression event subsequent to the first objective radiological progression, or death. Second progression may involve any of; objective radiological or symptomatic progression or death. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Symptomatic progression is assessed by investigators based on clinical examination.
Overall Survival (OS)	Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 30 months.	Time from randomisation until death due to any cause.
Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)	Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.	Number of responders according to blinded independent central review (BICR) assessment. Per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) for target lesions assessed by CT or MRI: Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response = CR + PR.
Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)	EORTC QLQ-C30 assessments performed at baseline then every ~6 weeks until objective radiological disease progression. Assessed up to a maximum of 30 months.	Change from baseline in global health status/quality of life (QoL) score assessed using a mixed model for repeated measures (MMRM) analysis, including all post-baseline global health status/QoL scores up to the latest scheduled visit where at least 20 patients on each treatment arm have a score. Global health status/QoL score is on a scale from 0 to 100. A higher score represents an improved health status/QoL.
Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm	Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.	Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Assessed in patients with a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).
Overall Survival (OS) at Final OS	Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 40 months.	Time from randomisation until death due to any cause.
Overall Survival (OS) at Extended OS	Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.	Time from randomisation until death due to any cause.

Countries

Bulgaria, China, Czechia, France, Hungary, Italy, Japan, Mexico, Peru, Poland, Romania, Russia, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States

Contacts

PRINCIPAL_INVESTIGATORMark Robson, MD

Memorial Sloan-Kettering Cancer Center, New York

Participant flow

Recruitment details

The first patient was enrolled on 27 March 2014 and the last patient on 30 October 2015. Patients were randomized at 125 centres across 19 countries in North America, South America, Europe and Asia.

Pre-assignment details

Screening occurred in 2 parts. Part 1: patients with unknown BRCA status were tested by Myriad. Part 1 screening failures were mostly due to no BRCA1/2 mutation detected. Part 2: patients with a known germline BRCA mutation were screened. 302 patients were randomized.

Participants by arm

Arm	Count
Olaparib 300 mg bd	205
Chemotherapy	97
Total	302

Baseline characteristics

Characteristic	Olaparib 300 mg bd	Total	Chemotherapy
Age, Continuous Age (years)	44 Years	44 Years	45 Years
Age, Customized <50	138 Participants	201 Participants	63 Participants
Age, Customized >=50-<65	56 Participants	86 Participants	30 Participants
Age, Customized >=65	11 Participants	15 Participants	4 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants	4 Participants	1 Participants
Race (NIH/OMB) Asian	66 Participants	94 Participants	28 Participants
Race (NIH/OMB) Black or African American	1 Participants	5 Participants	4 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	2 Participants	1 Participants
Race (NIH/OMB) White	134 Participants	197 Participants	63 Participants
Received prior chemotherapy for metastatic breast cancer No	59 Participants	87 Participants	28 Participants
Received prior chemotherapy for metastatic breast cancer Yes	146 Participants	215 Participants	69 Participants
Received prior platinum for breast cancer No	145 Participants	216 Participants	71 Participants
Received prior platinum for breast cancer Yes	60 Participants	86 Participants	26 Participants
Receptor status ER and/or PgR positive	103 Participants	152 Participants	49 Participants
Receptor status ER and PgR negative	102 Participants	150 Participants	48 Participants
Region of Enrollment Global BULGARIA	4 Participants	8 Participants	4 Participants
Region of Enrollment Global CHINA	32 Participants	41 Participants	9 Participants
Region of Enrollment Global CZECH REPUBLIC	11 Participants	12 Participants	1 Participants
Region of Enrollment Global FRANCE	5 Participants	9 Participants	4 Participants
Region of Enrollment Global HUNGARY	10 Participants	10 Participants	0 Participants
Region of Enrollment Global ITALY	17 Participants	24 Participants	7 Participants
Region of Enrollment Global JAPAN	15 Participants	24 Participants	9 Participants
Region of Enrollment Global KOREA	11 Participants	20 Participants	9 Participants
Region of Enrollment Global MEXICO	1 Participants	5 Participants	4 Participants
Region of Enrollment Global PERU	3 Participants	4 Participants	1 Participants
Region of Enrollment Global POLAND	10 Participants	15 Participants	5 Participants
Region of Enrollment Global ROMANIA	1 Participants	2 Participants	1 Participants
Region of Enrollment Global RUSSIAN FEDERATION	10 Participants	15 Participants	5 Participants
Region of Enrollment Global SPAIN	7 Participants	13 Participants	6 Participants
Region of Enrollment Global SWITZERLAND	6 Participants	8 Participants	2 Participants
Region of Enrollment Global TAIWAN	1 Participants	2 Participants	1 Participants
Region of Enrollment Global TURKEY	8 Participants	14 Participants	6 Participants
Region of Enrollment Global UNITED KINGDOM	8 Participants	12 Participants	4 Participants
Region of Enrollment Global UNITED STATES	45 Participants	64 Participants	19 Participants
Sex: Female, Male Female	200 Participants	295 Participants	95 Participants
Sex: Female, Male Male	5 Participants	7 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	159 / 205	73 / 97
other Total, other adverse events	196 / 205	85 / 91
serious Total, serious adverse events	37 / 205	15 / 91

Outcome results

Primary

Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame: Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)	7.0 Months
Chemotherapy	Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)	4.2 Months

Comparison: Study is sized to provide 90% power to detect a true treatment effect of PFS hazard ratio 0.653.p-value: 0.000995% CI: [0.43, 0.8]Log Rank

Secondary

Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)

Change from baseline in global health status/quality of life (QoL) score assessed using a mixed model for repeated measures (MMRM) analysis, including all post-baseline global health status/QoL scores up to the latest scheduled visit where at least 20 patients on each treatment arm have a score. Global health status/QoL score is on a scale from 0 to 100. A higher score represents an improved health status/QoL.

Time frame: EORTC QLQ-C30 assessments performed at baseline then every ~6 weeks until objective radiological disease progression. Assessed up to a maximum of 30 months.

Population: Subset of Full Analysis Set (FAS) consisting of all randomised patients with an evaluable baseline EORTC QLQ-C30 assessment and at least one evaluable post-baseline assessment

Arm	Measure	Value (MEAN)
Olaparib 300 mg bd	Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)	3.9 Score on a scale
Chemotherapy	Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)	-3.6 Score on a scale

p-value: 0.003595% CI: [2.5, 12.4]Mixed Models Analysis

Secondary

Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

Number of responders according to blinded independent central review (BICR) assessment. Per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1) for target lesions assessed by CT or MRI: Complete Response (CR) is defined as the disappearance of all target lesions; Partial Response (PR) is defined as \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response = CR + PR.

Time frame: Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.

Population: Evaluable For Response (EFR) Analysis Set consisting of all randomised patients with measurable disease at baseline, i.e. at least one measurable target lesion assessed by blinded independent central review (BICR)

Arm	Measure	Value (NUMBER)
Olaparib 300 mg bd	Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)	100 Participants
Chemotherapy	Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)	19 Participants

Secondary

Overall Survival (OS)

Time from randomisation until death due to any cause.

Time frame: Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 30 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Overall Survival (OS)	19.3 Months
Chemotherapy	Overall Survival (OS)	19.6 Months

p-value: 0.566595% CI: [0.63, 1.29]Log Rank

Secondary

Overall Survival (OS) at Extended OS

Time from randomisation until death due to any cause.

Time frame: Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Overall Survival (OS) at Extended OS	19.3 Months
Chemotherapy	Overall Survival (OS) at Extended OS	17.1 Months

p-value: 0.416795% CI: [0.67, 1.18]Log Rank

Secondary

Overall Survival (OS) at Final OS

Time from randomisation until death due to any cause.

Time frame: Survival status reviewed every 3 weeks until treatment discontinued, then every 8 weeks. Assessed up to a maximum of 40 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Overall Survival (OS) at Final OS	19.3 Months
Chemotherapy	Overall Survival (OS) at Final OS	17.1 Months

p-value: 0.513195% CI: [0.66, 1.23]Log Rank

Secondary

Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm

Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Assessed in patients with a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).

Time frame: Radiological scans performed at baseline then every ~6 weeks up to 24 weeks, then every ~ 12 weeks thereafter until objective radiological disease progression. Assessed up to a maximum of 30 months.

Population: Subset of Full Analysis Set (FAS) consisting of all randomised patients who were confirmed as Myriad CDx gBRCAm

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm	7.4 Months
Chemotherapy	Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm	4.2 Months

p-value: 0.000595% CI: [0.41, 0.78]Log Rank

Secondary

Time to Second Progression or Death (PFS2)

Time from randomisation to the earliest of the progression event subsequent to the first objective radiological progression, or death. Second progression may involve any of; objective radiological or symptomatic progression or death. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Symptomatic progression is assessed by investigators based on clinical examination.

Time frame: Second progression status reviewed every 8 weeks following the first objective radiological progression as per investigator assessment. Assessed up to a maximum of 30 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Time to Second Progression or Death (PFS2)	13.2 Months
Chemotherapy	Time to Second Progression or Death (PFS2)	9.3 Months

p-value: 0.003395% CI: [0.4, 0.83]Log Rank

Other Pre-specified

Time to First Subsequent Cancer Therapy or Death (TFST)

Time from randomisation to the earliest of first subsequent cancer therapy start date following study treatment discontinuation, or death.

Time frame: Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation. Assessed up to a maximum of 30 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Time to First Subsequent Cancer Therapy or Death (TFST)	9.4 Months
Chemotherapy	Time to First Subsequent Cancer Therapy or Death (TFST)	4.2 Months

Comparison: Supportive analysis to PFS.p-value: <0.000195% CI: [0.24, 0.47]Log Rank

Other Pre-specified

Time to First Subsequent Cancer Therapy or Death (TFST) at Extended OS

Time from randomisation to the earliest of first subsequent cancer therapy start date following study treatment discontinuation, or death.

Time frame: Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Time to First Subsequent Cancer Therapy or Death (TFST) at Extended OS	9.4 Months
Chemotherapy	Time to First Subsequent Cancer Therapy or Death (TFST) at Extended OS	4.3 Months

Comparison: Supportive analysis to PFS.p-value: <0.000195% CI: [0.27, 0.5]Log Rank

Other Pre-specified

Time to Second Subsequent Cancer Therapy or Death (TSST)

Time from randomisation to the earliest of second subsequent cancer therapy start date following study treatment discontinuation, or death.

Time frame: Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation. Assessed up to a maximum of 30 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Time to Second Subsequent Cancer Therapy or Death (TSST)	14.3 Months
Chemotherapy	Time to Second Subsequent Cancer Therapy or Death (TSST)	10.5 Months

Comparison: Supportive analysis to PFS2.p-value: 0.000295% CI: [0.38, 0.74]Log Rank

Other Pre-specified

Time to Second Subsequent Cancer Therapy or Death (TSST) at Extended OS

Time from randomisation to the earliest of second subsequent cancer therapy start date following study treatment discontinuation, or death.

Time frame: Subsequent cancer therapy status reviewed every 8 weeks following study treatment discontinuation until Sep 2017 (final OS DCO), then every 3 months. Assessed up to a maximum of 64 months.

Population: Full Analysis Set (FAS) consisting of all randomised patients

Arm	Measure	Value (MEDIAN)
Olaparib 300 mg bd	Time to Second Subsequent Cancer Therapy or Death (TSST) at Extended OS	14.3 Months
Chemotherapy	Time to Second Subsequent Cancer Therapy or Death (TSST) at Extended OS	10.5 Months

Comparison: Supportive analysis to PFS2.p-value: <0.000195% CI: [0.4, 0.72]Log Rank

Assessment of the Efficacy and Safety of Olaparib Monotherapy Versus Physicians Choice Chemotherapy in the Treatment of Metastatic Breast Cancer Patients With Germline BRCA1/2 Mutations.

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Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

Adjusted Mean Change in Global Health Status/Quality of Life (QoL) Score From the European Organisation for Research and Treatment of Cancer - Quality of Life Questionnaire (EORTC QLQ-C30)

Objective Response Rate (ORR) Using Blinded Independent Central Review (BICR) Data Assessed by Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1)

Overall Survival (OS)

Overall Survival (OS) at Extended OS

Overall Survival (OS) at Final OS

Progression-free Survival (PFS) Using Blinded Independent Central Review (BICR) According to Modified Response Evaluation Criteria In Solid Tumours (RECIST v1.1) in Patients Confirmed as Myriad CDx gBRCAm

Time to Second Progression or Death (PFS2)

Time to First Subsequent Cancer Therapy or Death (TFST)

Time to First Subsequent Cancer Therapy or Death (TFST) at Extended OS

Time to Second Subsequent Cancer Therapy or Death (TSST)

Time to Second Subsequent Cancer Therapy or Death (TSST) at Extended OS